Cartridge and system for storing and dispensing of reagents

ABSTRACT

By arranging reagents needed for a specific reaction in separate distinct chambers in a reagent cartridge and combining several such reagent cartridges in a cassette in a format that matches that of commonly used microtitre plates. e.g. the 96 well format or other standard formats. several drawbacks of well-known procedures can be eliminated.

This application is the national phase under 35 U.S.C. §371 of PCTInternational Application No. PCT/SE97/01562 which has an Internationalfiling date of Sep. 16, 19997 which designated the United States ofAmerica.

THE FIELD OF THE INVENTION

The present invention concerns a device and a procedure for storing anddispensing chemical reagents. In particular, the invention concerns adevice and a procedure for storing and dispensing biochemical reagentsused in small volumes and therefore sensitive to contamination,oxidation and cross-reactions between the reagents.

BACKGROUND OF THE INVENTION

Immunological methods such as RIA, EIA and ELISA have found widespreadapplication in medical diagnostics during recent decades. (RIA, EIA andELISA are abbreviations for Radioactive Immuno Assay, Enzyme LinkedImmuno Assay and Enzyme Linked ImmunoSorbent Assay respectively). Thesemethods quickly developed into standard procedures. To meet the demandfor efficient handling with both manual and automated pipettes, as wellas in detection instruments, standardised reaction vessels that couldhandle several samples at the same time were developed. These vesselsare referred to as multi-sample plates in the remainder of thisdocument.

A microtitre plate commonly consists of a rectangular plate formed frominjection molded polystyrene plastic. The plate contains a number ofhollows arranged in a grid. These hollows are known as wells and act asreaction vessels for individual chemical reactions. The three mostimportant standards of microtitre plates are their outer dimensions thatallow them to fit in standard instruments, their so-called grid spacing,which is the distance between the centre of one well to the centre ofthe adjacent well in the same row or column in the grid, and theposition of the wells in relation to each other and to the outer edgesof the plate. The most widely used microtitre plate format isapproximately 128×85×14 millimeters with 96 wells arranged in a grid ofeight rows and 12 columns. The grid spacing between wells is about ninemillimeters. However, several other divisions are found within the abovecited format. Usually encountered are also plates with 192, 384 or evenmore wells. Microtitre plates constituting one half of the above citedformat are also in use. The most recent addition to this variety ofmulti-sample plates are the multi-sample plates used in so calledmultiple array technology, where extremely small volumes are ejectedonto a surface, e.g. an absorbent surface. Examples of this technologyinclude the multi-sample plates or sheets used in assays and proceduresutilizing hybridization to High Density Oligonucleotide Arrays, e.g.detection of genetic mutations, genome screening or sequencingoperations. Multi-sample plates used in the multi array technology arealso referred to as nanotitre plates or nano-well plates. Also siliconchips or wafers, having areas for receiving reagents and samples, shouldbe included under the definition “multi-sample plates”.

Microtitre plates with wells arranged in a grid form are the mostcommonly used form of multi-sample plate. However, other arrangements ofwells, such as circular forms, are also found in multi-sample plates.

When working routinely with microtitre plates, especially in areas ofclinical application, the user aims to increase handling speed, i.e. thethrough-put speed of samples, by introducing various levels of automatedsystem for the different steps. One such step is the handling ofreagents.

Reagents can be handled with manually operated pipettes such as thoseknown as plunger pipettes. For work with microtitre plates,multi-channel pipettes have been developed. These allow manual pipettingin complete rows or columns of wells in a single action. In aiming tofurther automate this pipetting work, a range of electronic instrumentsof varying complexity have also been developed. Examples include plungerpipettes with electronically driven step motors and multi-channelpipettes and dispensers with different types of pumps.

A high level of automation can be achieved by integrating units thatposition the reaction vessel in relation to the dispensing mouthpieceand units for the computerised control of this positioning in relationto the pipetting process. An instrument with such a high level ofautomation is usually called a pipetting robot. In other words, apipetting robot comprises three main functional units. Firstly, adispensing unit that comprises one or more individual precision pumps.The function of this type of precision pump is to dispense a specifiedvolume of liquid through the mouthpiece at a specific time. Secondly, apipetting robot comprises a positioning unit that orientates theposition of the dispensing mouthpiece in relation to the reaction vesselat the exact moment of dispensing. Thirdly, an electronic control unit.

The difficulty in constructing a pipetting robot of the kind describedin the previous paragraph is to achieve a sufficiently high level ofprecision regarding a number of key functions. One key function of apipetting robot is the accuracy of the average amount of liquiddispensed and the standard deviation between different pipetting actionsIn general, the degree of accuracy is less when pipetting small volumesthan when pipetting large volumes. A further key function is naturallythe speed of operation measured as the number of completely dispensedsamples per unit of time. It has proven difficult to construct robotsthat are both accurate when dispensing small volumes and sufficientlyquick to meet the demands of molecular biological work in a clinicalenvironment, for example.

In addition to these main functional characteristics of a pipettingrobot, there are other characteristics that can also be important.Examples of such characteristics are purchase price, cost effectivenessfor small series of samples, instrument size, and the requirement forcleaning the mouthpiece and other parts to help prevent contamination byforeign material and material from previous pipetting actions. Inaddition, the reaction vessel, the sample and the chemicals should beprotected from exposure to air-borne particles that can carry suchcontaminating material.

Today, there are pipetting robots that differ with regard to whetherthey have separate mouthpieces for suction and dispensing or whether thesame mouthpiece is used for both functions. The first type incorporatesone or more suction mouthpieces connected with one or more liquidreservoirs, i.e. vessels from which the reagents shall be dispensed.These reagents pass from this vessel through the suction mouthpiece andvia the dispenser unit to one or more dispensing mouthpieces from wherethey are transferred to the reaction vessel. This type of pipettingrobot is subsequently referred to as a pump dispenser.

The second type of pipetting robot features one or more combined suctionand dispensing mouthpieces. This type has a stand-alone liquidreservoir. The chemical reagents are drawn up from the sample vessel tothe mouthpiece and are then dispensed into the reaction vessel with thesame mouthpiece. This type of pipetting robot is subsequently referredto as a pipette dispenser.

The pump dispenser type of pipetting robot meets normal demands foraccuracy, even when dispensing small volumes. It does not, however,fulfil the demands for speed of operation. In contrast, the pipettedispenser type of pipetting robot does meet normal demands for speed ofoperation. However, it does not normally meet the demands for a highdegree of accuracy, which is one of the main pre-requisites.

A further problem is that neither type of pipetting robot is costeffective for small series of samples, i.e. handling about 500 samplesor less. Protection against air-borne contamination can also be aproblem. In addition, pump dispensers are very expensive to purchase andit is often difficult to clean their mouthpieces.

Those operations relevant to this invention that are today performedwith conventional techniques, either manual or automatic, are, inchronological order the industrial synthesis of reagents, their storagein large packs, transport of these packs to the user, measuring out therelevant reagent volumes and dispensing these volumes in the appropriatesample wells or reagent vessels, such as the multi-sample plate, forexample. When the actual sample has been applied and mixed with thereagents in the wells or equivalent intended for use in the multi-sampleplate, this vessel is fully prepared and placed in an instrument orother location for incubation.

Pipetting robots are mainly used for two operations in this chain ofevents. They are used partly in connection with the industrial synthesisof reagents and their storage in large packs. These robots arefrequently the pump dispensing type and are often large, expensive andrelatively slow. They are, however, very accurate and form part of aquality-assured process with regard to all possible contaminationthreats, risks of mix-up, and similar hazards. Pipetting robots are alsoemployed in the user's laboratory for measuring out relevant reagentvolumes and dispensing these in, for example, a multi-sample plate wherea certain analysis is to be performed. These pipetting robots can be ofdifferent types but they must be quick and cannot be bulky or expensive.For these reasons they are usually not as accurate as the former typementioned. One problem in the user's laboratory can be the risk ofcontamination due to particles normally carried in the air, aerosols,splashing or via the mouthpiece or other component. The risk of mixingup bulk packs, for example, is especially great when many short seriesof samples are run or many different users are involved. In thiscontext, sample means a patient sample, test material or otheringredient chosen by the user, of which the sample forms a part of thereagent mixture that is to be prepared.

It would be extremely advantageous if one could combine the advantagesof the pipetting robot used in industrial context, i.e. accuracy andsecurity with regards to contamination, mix-up and similar risks, withthe advantages of the pipetting robot employed in the user's laboratory,i.e. speed, low price and compactness.

This could be achieved by replacing the storage of industriallysynthesised reagents in bulk packs with storing the reagents directly inthe end user's reaction vessel, which is then transported to the user'slaboratory with the ready mixed reagents. Only ample application thentakes place in the laboratory. This ensures rapid, accurate and securehandling in this environment. The need for a pipetting robot is thuseliminated and the advantages of low price and compact size can thus beconsidered to have been fulfilled.

This solution is nevertheless associated with two disadvantages.Firstly, different end users prefer different types and manufacturers ofreaction vessels, which makes efficient industrial handing difficult.Secondly, pre-mixing the reagents in the reaction vessel can startvarious chemical processes that reduce sensitivity and shelf life, whichcan in turn lead to incorrect sample results.

The Prior Art

U.S. Pat. No. 3 554 705 describes a chemical package or crude reagentcartridge containing different reagents in separate storage chambersadapted for communication with, said compartments being closed withrestraining means preventing the premature movement of the prepackedreagents from each of said storage chambers. This construction resemblesthe blister packaging system, used for solid and particulate matter.Although no volumes are mentioned in the description and claims, theconstruction of the storage chambers makes it clear, that they areintended to contain volumes in the order of magnitude of milliliters andin no case volumes so small, that they resist gravity and requirecentrifugation to leave the cartridge.

EP 678 745 A1 represents a more recent approach where a sample istransferred through centrifugation from a pointed vessel to a reactionvessel, where the latter is covered by a membrane and the pointed vesselpenetrates said membrane. This system does not, however, concern thestorage and dispensing of reagents and lacks the benefits, associatedwith the present invention.

A number of special problems arise when using the extremely smallvolumes that are typical in this context, i.e. in the order of a few μland less. For example, the volumes are so small that a force is requiredto detach them from the sides of the vessel or container in which theyare stored. These volumes are often protected from evaporation andoxidation by a layer of wax or viscous oil. In practice, a force greaterthan gravity is needed to transfer the reagent from the dispensingcontainer or device to the reaction vessel.

The aim of the present invention is to provide a device that conformswith current standards and working methods, especially those applied inbiochemical analysis. Biochemical analysis refers to procedures todetect biochemical components, e.g. proteins, enzymes, andoligonucleotides, or for detecting the presence of specific cells, e.g.disease-causing organisms or cells that have undergone a pathogenictransformation, such as cancer cells. In particular, the aim of theinvention is to provide a system that permits the safe andcontamination-free storage of reagents, accurate dispensing with a highlevel of reproducibility, and simple handling that minimises the numberof user operational steps. One aim is to eliminate the need for manualor automated pipetting by the user, i.e. in the laboratory where theanalysis is performed.

SUMMARY OF THE INVENTION

The drawbacks of current techniques described above are overcome by thepresent invention as described in the attached claims. In particular,the invention concerns a device and a procedure for storing anddispensing biochemical reagents used in small volumes and thereforesensitive to contamination, oxidation and cross-reactions between thereagents.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is described in greater detail with reference to theenclosed drawings, in which

FIG. 1a shows a schematic cross-section of a reagent cartridge accordingto the present invention,

FIG. 1b shows a perspective view of the cartridge in FIG. 1a,

FIG. 2 shows schematically how reagent cartridges can be combined with amulti-sample reaction plate according to the invention,

FIGS. 3A and 3B show two embodiments of the invention,

FIG. 4 shows a schematic cross-section of an embodiment where one of thereagents is enclosed in an open-ended capillary, contained in one of thechambers,

FIG. 5 shows a cut-away perspective view of one preferred embodiment ofthe invention where the reaction cartridges are arranged in the samenumbers and positions as the reaction vessels in a multi-sample plateknown as a microtitre plate.

DESCRIPTION OF THE INVENTION

According to the invention, the reagents are stored and dispensed usinga device capable of containing two or more reagents, separated from eachother and protected from the atmosphere. The reagents are then removedfrom the device through centrifigation, optionally after mechanicallyremoving or relocating means, such as covers, closures or barrierssealing the chambers of the device. Said means can include plugs orvalves, films, membranes and also viscous liquids or waxes.

The reagent chambers according to the present invention comprise anydistinct, physically separated volume, generally containing volumes lessthan about 100 μl. In wash steps, the volume can nevertheless be larger,e.g. 200-500 μl. In specific, preferred embodiments, the volumes areconsiderably smaller, in the interval of 0.001-0.5 μl.

FIG. 1a shows schematically a reagent cartridge (1) with its distinctchambers (2), in which small amounts of reagents are stored. Thesereagents are marked in black. The reagents are separated from each otherand from the surrounding atmosphere by seals (3) of appropriate materialsuch as wax or viscous organic compounds. The chambers (2) canthemselves be sealed off with other types of closures (4) such as plugsor thermoplastic membranes.

FIG. 1b shows the above embodiment in a perspective view, illustrationone spatial arrangement of the chambers. Obviously the number andconfiguration of the chambers can vary within the scope of theinvention.

FIG. 2 shows how more than one reagent cartridge (1A and 1B) can bearranged on the holder of a cassette so that the numbers and positionsof the reagents cartridges match the numbers and positions of thereaction vessels in the multi-sample plate into which the reagents areto be dispensed, 1A and 1B show two distinct stages of operation. Inreagent cartridge 1A, the seal of the left-hand chamber has beendetached and the reagent transferred to the vessel, while the seal 4 ofthe right-hand chamber is still in place and all the reagents and theirsealing layers (3′, 3″) remain in place. In 1B, seals 4 and 3′ have beenremoved, but seal 3″ and the final reagent remain.

According to an embodiment of the invention, the reagent chambers canadditionally be closed by a detachable or movable cover, plug or abreakable seal or film. FIGS. 3A and 3B show schematically twoembodiments of the invention where seal 4 is operated and openedmechanically. 3A shows one embodiment where all seals opensimultaneously. 3B shows another embodiment that allows seals to beopened independently of each other.

One embodiment, concerning the opening of the closing means, comprisesplates with a three-dimensional pattern, e.g. grooves and ridges,engaging with parts of the closing means, extended through the reagentcartridge (FIG. 3A and B). These plates will be called “press-plates” inthe following. Such a press-plate can be designed in various fashion,for example be assigned color codes, corresponding to different weightsand/or patterns. Preferably, these press-plates are actuated during thecentrifugation of the assembly consisting of a receiving multi-sampleplate, reagent cartridges and press-plate. Optionally, the press-platecan be depressed manually with or without mechanical aids. The benefitof actuation by centrifugation or using optional mechanical aids, isthat the opening of the cartridges, corresponding to the pattern of thepress-plate, is guaranteed to be simultaneous and to include allcartridges concerned.

According to one specific embodiment, shown schematically in FIG. 4, oneor several of the reagents is enclosed in an open-ended capillary,contained in one of the chambers. This is specially preferred whendispensing very small volumes of reagent, e.g. volumes in the intervalof 0.001-0.50 μl. This arrangement is also beneficiary in protecting asmall reagent volume from environmental influences. Volumes in thisinterval are further very difficult to measure exactly, as physicalinteractions, such as surface tension, adsorption and hydrodynamicbehaviour exert a considerable influence on the droplet.

In measuring, storing and dispensing extremely small volumes, forexample volumes less than 50 nanoliters, special difficulties areencountered. As previously described, such volumes are hitherto handledin a satisfactory manner only by ink-jet like apparatuses. It has beenshown, by the present inventor, that the behaviour of such small volumesis dependent on the relation between volume and the surface area incontact with said volume. For example in the filling and cutting of thincapillaries, the cutting itself causes a compression of the capillaryand thus a displacement of liquid. Surprisingly, when the surface areain contact with the liquid is maximized, for example by using a longerand thinner capillary in stead of a shorter and thicker, the deformationduring cutting and thus liquid displacement is reduced. It isparticularly preferred to introduce a core in the capillary and thusform a volume, enclosed by the outer walls of the core and the innerwalls of the capillary. This is true regardless of shape of thecapillary, however, circular or oval cross sections have practicalbenefits. Additionally, when extending the length of the liquidfilledsections, the effect of the cutting has less effect on the accuracy. Thetechnology of cutting segments of a predetermined length is also welldeveloped and high accuracy and reproducibility is acheived.

The capillary in FIG. 4 can also, within the scope of the presentinvention, be a multi-lumen capillary, suitable for independentintroduction in a reaction vessel or constitute part of a reagentcartridge, as a capillary contained in one chamber of a cartridge.

FIG. 5 indicates one preferred embodiment of the invention, i.e. acassette where several reagent cartridges are arranged so that theirnumbers and positions match the numbers and positions, or fractions ofsaid numbers and positions of the reaction vessels in a multi-sampleplate such as a microtitre plate. Ideally, the reagent cartridges arearranged in rows of eight and columns of twelve in one cassette that canbe placed on or partially in a microtitre plate of the commonly used 96well format. It is however contemplated, that the cartridges correspondto a fraction of this or other commonly used formats. Reagent cartridgescan be assembled in cassettes comprising 3×8 cartridges or in strips ofcartridges, single file, of various lengths.

When producing the reagent cartridges according to the invention, theymay comprise separate units when being filled with reagents, yet aresuitable for combining in a cassette so that several can be usedtogether. This allows effective and flexible production, especially incases, where the cartridges are filled with different reagents ordifferent reagent concentrations. Thus, a large series of cartridgeswith identical or similar composition can be produced to be latercombined in cassettes intended for specific analyses. A simple exampleof this is the production of a cassette to use in an optimisationreaction. Large series of reagent cartridges with differentconcentrations of a reagent can be produced and then arranged asconcentration gradients in the different rows or columns of themulti-sample plate.

The seals to the open chambers referred to previously are suitable foropening by any of the following means: increased temperature,centrifuging the reagent cartridge or application of an external force.Increasing temperature, for example, can involve allowing thetemperature of the reagent cartridge to rise from a storage temperatureof 18 18° C. or below to a temperature of −4° C. +8° C., or +20° C., orheating it to a higher temperature. Centrifugation can be performed atdifferent speeds so that the force used to open the seals can becontrolled. Arrangements for applying external force cover any kind ofmechanical influence, including the previously described “press-plates”.

According to one preferred embodiment, the reagent cartridge includes atleast one of the following reagents: DNA polymerase, RNA polymerase,reverse transcriptase, urasil-N-glycolase, DNA ligase, catalyticribonucleic acid, deoxyribonucleotides, ribonucleotides,oligonucleotides, fluorescent dyes, bovine serum albumin, formamide,glycerol, buffer substances, ammonium sulphate, dimethylsulphoxide,anionic detergents, and non-ionic detergents for a specific reaction.

The invention also comprises a system for storing and dispensingchemical reagents, especially small volumes of biochemical reagents. Itis characterised by the reagents being located in distinct chambers in areagent cartridge and isolated from the surrounding atmosphere, and bythe arrangement of several similar reagent cartridges so that theirnumbers and positions reflect the numbers and positions of reactionvessels known as wells contained in a multi-sample plate.

Reactions whose execution is especially suitable for using this reagentcartridge or system according to the described invention are as follows:A polymerase chain reaction (PCR), a ligase chain reaction (LCR), a“gapped-LCR-reaction”, a nucleic acid sequence-based amplification(NASBA), a self-sustained sequence replication (3SR), a transcriptionmediated amplification (TMA), a strand displacement amplification (SDA),a target amplification, a signal amplification, or a combination of anyof the above.

A reagent cartridge or system according to the present invention isespecially applicable for detecting a nucleotide sequence or nucleotidesequences forming part of any of the following nucleic acids: a virusgenome, nucleic acids originating in bacterial cells or eukaryoticcells, or coding regions from cells of vertebrates used for tissuetyping.

A reagent cartridge or system according to the presented invention isespecially applicable for detecting any of the following viruses: humanimmunodeficiency virus (HIV), human papillomavirus, hepatitis viruses,cytomegalovirus or similar.

A reagent cartridge or system according to the presented invention isespecially applicable for detecting cells from any of the followinggenera: Chlamydia, Rickettsia, Mycobacterium, Haemophilus, Neisseria.Streptococcus, Listeria, Cryptococcus. Coccoides, Blastomyces,Histoplasma or similar.

A reagent cartridge or system according to the presented invention isespecially applicable for detecting cancer cells.

The present invention further comprises kits for performing any one ofthe reactions or assays described above, such a kit comprising thenecessary reagents, prepacked in cartridges optionally assembled as oneor several cassettes, optionally reaction vessels and actuating meanssuch as press-plates and instructions for use.

One preferred embodiment of the invention is a cassette used whenperforming chemical reactions, particularly biochemical analyses usingmulti-sample plates known as microtitre plates. It is characterised bythe cassette consisting of a number of reagent cartridges arranged sothat their numbers and positions match the numbers and positions ofreaction vessels known as wells contained in a multi-sample plate suchas the conventional 96 hole microtitre plate format.

Finally, the invention includes a procedure for dispensing reagents,principally biochemical reagents used in small amounts during analysesthat employ multi-sample plates. This procedure includes the followingsteps:

at least two reagents are delivered, physically separated from eachother in a reagent cartridge,

several reagent cartridges are arranged in at least one cassette so thattheir numbers and positions match the numbers and positions, orfractions of said numbers and positions, of reaction vessels in amulti-sample plate such as a microtitre plate,

the cassette or casettes is/are combined with a multi-sample plate,

the reagent cartridges are emptied of their contents.

According to one preferred embodiment, emptying takes place in severalsteps, for example, by the sequential execution of one or more of thefollowing measures: increasing temperature, centrifugation, andapplication of an external force.

Although the invention has been described with regard to its preferredembodiments, which constitute the best mode presently known to theinventors, it should be understood that various changes andmodifications as would be obvious to one having the ordinary skill inthis art may be made without departing from the scope of the inventionwhich is set forth in the claims appended hereto.

What is claimed is:
 1. A reagent cartridge for storing and dispensingbiochemical reagents used in such volumes that centrifugation isrequired to detach the reagents from the cartridge, comprising at leasttwo separate distinct chambers for reagents suitable for direct additionto a reaction system; and a seal in at least one o f the chambers thatseals the reagent from the surrounding atmosphere, whereby the reagentcartridge can be combined in a cassette comprising of several reagentcartridges.
 2. The reagent cartridge according to claim 1, wherein atleast one of the chambers has an orifice that can be sealed with aopenable closure that can be opened without affecting the surroundingsof the orifice or other sealed chambers arranged in the same device. 3.The reagent cartridge according to claim 2, wherein the sealed closureis opened by increasing temperature, centrifugation, application of anexternal force or a combination thereof.
 4. The reagent cartridgeaccording to claim 1, wherein the reagent volumes are in the range of 1to 200 μl.
 5. The reagent cartridge according to claim 1, furthercomprising at least one of th e following reagents: DNA polymerase, RNApolymerase, reverse transcriptase, urasil-N-glycolase, DNA ligase,catalytic ribonucleic acid, deoxyribonucleotides, ribonucleotides,oligonucleotides, fluorescent dyes, bovine se rum albumin, formamide,glycerol, buffer substances, ammonium sulphide, dimethylsulphoxide,anionic deter gents, or non-ionic detergents.
 6. The reagent cartridgeaccording to claim 1, wherein a separate capillary is contained in atleast one of said fluid chambers.
 7. The reagent cartridge according toclaim 6, wherein the separate capillary is a multi-lumen capillary. 8.The reagent cartridge according to claim 6, wherein the separatecapillary comprises an outer wall and a core, defining the capillaryspace between the wall and core.
 9. A system for storing and dispensingbiochemical reagents in cartridges, said reagent volumes requiringcentrifugation to be detached from said cartridges, comprising reagentslocated in distinct chambers in a reagent cartridge and isolated fromthe surrounding atmosphere, wherein several such reagent cartridges arearranged so that their numbers and positions reflect the numbers andpositions or fractions of reaction vessels known as wells contained in amulti-sample holder.
 10. The system according to claim 9, wherein thereagent cartridges are arranged in rows and columns according toconventional microtitre plate format or other standard formats.
 11. Thesystem according to claim 9, wherein at least one of the reagents issupplied in the form of a concentration gradient by arranging thereagents in different concentrations in different reagent cartridges.12. The system according to claim 9, wherein said reagents are reagentsfor at least one of the following reactions: a polymerase chain reaction(PCR), a ligase chain reaction (LCR), a “gapped-LCR-reaction”, a nucleicacid sequence-based amplification (NASBA), a self-sustained sequencereplication (3SR), a transcription mediated amplification (TMA), astrand displacement (SDA), target amplification, a signal amplification,or a combination of any of the above.
 13. The system according to claim12, wherein said reagents are for the determination of the presence orabsence of a nucleotide sequence or nucleotide sequences, and whereinthe nucleotide sequence or nucleotide sequences are part of any of thefollowing nucleic acids: a virus genome, nucleic acids originating inbacterial cells or eukaryotic cells, or coding regions from cells ofvertebrates used for tissue typing.
 14. The system according to claim 9,wherein said reagents are for the detection of any one of the followingviruses: human immunodeficiency virus (HIV), human papillomavirus,hepatitis viruses, or cytomegalovirus.
 15. The system according to claim9, wherein said reagents are for the detection of cells of any of thefollowing genera: Chlamydia, Rickettsia, Mycobacterium, Haemophilus,Neisseria, Streptococcus, Listeria, Cryptococcus, Coccoides,Blastomyces, or Histoplasma.
 16. The system according to claim 9 whereinsaid reagents are or the detection of cancer cells.
 17. A cassettecomprising reagent cartridges used to perform biochemical reactionsusing reagents in volumes requiring centrifugation to detach thereagents from the cartridge, comprising a number of reagent cartridgesaccording to claim 1 arranged so that their numbers and positions matchthe numbers and positions or fractions of said numbers and positions ofreaction vessels known as wells in a multi-sample plate.
 18. Thecassette according to claim 17, wherein the reagent cartridges arearranged in rows and columns according to the conventional microtitreplate format or other standard formats.
 19. A method for dispensingreagents which comprises delivering at least two reagents that arephysically separated from each other into a reagent cartridge, so thatat least one of the reagents in the reagent cartridge is contained in achamber having a seal that seals the reagent from the surroundingatmosphere, wherein several reagent cartridges are arranged in acassette so that their numbers and positions match the numbers andpositions of fractions of the numbers and positions of reaction vesselsin a multi-sample plate, combining at least one cassette containing thereagent cartridge with a multi-sample holder, emptying the reagentcartridge their contents by centrifugation.
 20. The procedure fordispensing reagents according to claim 19, wherein the cartridges areemptied in several steps.
 21. The procedure for dispensing reagentsaccording to claim 20, wherein the cartridges are emptied by thesequential execution of one or more of the following measures:increasing temperature, centrifugation, application of an external forceor a combination thereof.
 22. A method of preparing a cassette systemfor dispensing reagents which comprises delivering at least two reagentsthat are physically separated from each other into a reagent cartridge,so that at least one of the reagents in the reagent cartridge iscontained in a chamber having a seal that seals the reagent from thesurrounding atmosphere, wherein several reagent cartridges are arrangedin a cassette so that their numbers and positions match the numbers andpositions of fractions of the numbers and positions of reaction vesselsin a multi-sample plate.
 23. A method of dispensing reagents whichcomprises combining at least one cassette of claim 17 with amulti-sample holder, emptying the reagent cartridge their contents bycentrifugation.